Sema3A is able to orient the growth of cortical apical dendrites towards the pial surface of neocortex and this requires the function of soluble guanylyl cyclase (SGC) and cGMP-dependent protein kinase (PKG). In developing cortical neurons, SGC is asymmetrically localized to the site where apical dendrites subsequently emerge. A series of experiments is proposed in this project to test the hypothesis that Sema3A regulation of apical dendrite orientation involves the assembly of SGC-containing multimolecular complex at the presumptive apical pole of the cortical neurons. Components of this SGC-activated multimolecular complex may include the putative mammalian homologues of yeast proteins known to be involved in polarized bud growth. Activation of such spatially restricted signaling complex drives not only the polarized, but also oriented, growth of apical dendrites. This hypothesis will be explored in the context of the following specific aims: Aim I. To examine the subcellular localization of SGC in response to a Sema3A gradient and to determine if the asymmetrical localization of SGC is required for Sema3A-oriented apical dendrite outgrowth. Aim II. To test the hypothesis that neuronal polarity is established by a mechanism analogous to the bud-site selection in yeast by determining the subcellular localization of putative mammalian homologues of yeast proteins in developing cortical neurons. Aim III To determine the role of Rap1 GTPase, the mammalian homologue of Bud1p, in the dendritic development of cortical neurons.